Dengue virus (DENV) is the most important mosquito-bome viral disease affecting humans today. An estimated 100 million people are infected with dengue virus annually, leading to dengue fever and dengue hemorrhagic fever (DHF). Since there are an estimated 2.5 billion people living in areas at risk for epidemic transmission and since both the number of DENV infections and the proportion of infections resulting in DHF have escalated in the past 20 years, the absence of anti-DENV therapeutics or an anti-DENV vaccine is a growing public health concern. We recently discovered two independent series of inhibitors of DV entry based on disubstituted pyrimidine and alpha-ketocyanohydrazone scaffolds, both of which appear to block the fusion step of virus entry. Here, we propose to utilize a combination of focused medicinal chemistry, biochemistry, and virology to understand the structure-activity relationships governing the anti-DENV activity of these compounds as well as their mechanism of action.